An educational blog designed to introduce and facilitate industrial hygienists' involvement in quantitative risk assessment - especially exposure assessment and the specific area of exposure modeling.

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Sunday, April 13, 2014

Hormesis for Setting OELs: Are you kidding me?

I have been interested in the topic of hormesis for a long
time.Even though I am not a toxicologist,
some years ago I was responsible for running an inhalation toxicity laboratory
in a large chemical company.When I
mentioned hormesis to my toxicologist colleagues in those days the standard
response was for them to roll their eyes and dismiss it as nonsense and
definitely non-science.Their minds were
closed to the ideas presented within this concept.I am bringing it up in this blog in the hope
that you will be more open to the possibilities it might present.

I am reproducing the graph I put into the blog last week for
convenience. It shows hormesis as one
of 4 possible models presented for low-dose extrapolation.

Indeed, hormesis is an old concept and is actually referred
to in the famous 16th century quote from Paracelsus that has been paraphrased
over the years as: “The dose makes the poison”.
His actual quote is:

Poison is in everything, and no thing is without poison. The dosage
makes it either a poison or a remedy.
[emphasis added]

I challenge you to think of any medicine that is NOT; by
definition and design, good for you at a reasonably low therapeutic dose and a poison at high dose. A common, but
very real, example in most of our medicine chests is acetaminophen (common
trade name: Tylenol). This is a ubiquitous
OTC drug, which works quite well for aches and pains and fever at the
recommended dose, but is deadly to our livers and lives in doses that are only
a 3-5 times higher.

All micronutrients also follow the hormesis curve. For example, consider the effect on your eyes
of not having enough vitamin A in your diet or as a separate supplement.

Now consider a very common industrial chemical:
ethanol. Many of us enjoy the acute
effects of ingesting ethanol (aka ethyl alcohol, drinking alcohol) as the
active ingredient in beer, wine and hard liquor. Most of us know that drinking too much can be
acutely and chronically toxic resulting in alcohol poisoning and liver disease. What some may not realize is that, in
moderation (i.e., a “low-dose” of 2 drinks per day), one can enjoy the mood
altering features of this chemical while also benefiting from an increase in
cardiovascular health over those who do not drink any alcohol. Most Doctors admit that this is true but have
fallen short of recommending that nondrinkers start drinking for various reasons. I will not go into the details of their
reasons or the scientific evidence here but the benefits have been fairly well
established to be true by research.

There have also been paper published in which low doses of very strong carcinogenic substances have results in less cancer (versus untreated controls) in animal experiments at low-dose.

Professor Edward J. Calabrese, School of Public Health,
University of Massachusetts, Amherst has devoted a considerable portion of his
professional career to the study of hormesis.
He has written extensively about it and has organized workshops in which
he always invites all sides to this discussion. Most of these discussions are summarized and
presented on the web site: http://www.belleonline.com/

Dr. Calabrese once asked me to present my opinion of hormesis in low-dose
extrapolation and risk assessment for a publication and one of Dr. Calabrese’s
workshops:

My conclusion from almost 10 years ago remains the same today;
specifically: “… we will only be able to
move forward with hormesis as a default hypothesis [for low-dose extrapolation]
after the development and use of tools from the realm of molecular biology.”

The science of the “omics” (genomics, proteomics, etc) has
come a long way in the intervening years but from what I can tell it has not explicitly
addressed the above issue. Indeed,
unless and until we really understand the effect of low dose at the human
tissue level, we will not know which low-dose response curve is the best as
either a default model or specifically applied to any substance.

Until that happy day I believe that we need to rely on a
science-informed political process to do the best we can to describe the actual
risk at the OEL along with the frank admission of the uncertainty in that
description.

The linear extrapolation assumption (i.e., no hormesis, no threshold) is a convenient one mathematically. Perhaps convenience trumps accuracy for some folks?

In ecology, the hormesis idea was described as a subsidy/stress pattern by Eugene Odum several decades ago. Basically, it stated that a small amount of a stress (e.g., fertilizer, pollutant, fishing) could lead to an improvement in whichever measure of ecosystem performance was being observed, and that this gave way to detrimental changes at some higher exposure.

Seems like this process reflects changes in controlling mechanisms - which is probably what you see as potential clarifications resulting from -omics. Response results from one enzyme system/one species being "benefitted" at low exposure, but other systems/species then affected at higher exposures.